FIELD OF THE INVENTION
This invention is concerned with new pharmaceutical formulations for the treatment of depressed warm-blooded animals, including man, containing as active ingredient a compound of the Formula III: ##STR3## wherein A is a group selected from --(CH.sub.2).sub.2 --; --(CH.sub.2).sub.3 --; --(CH.sub.2).sub.4 --; --(CH.sub.2).sub.5 --; ##STR4## wherein R is ethyl, vinyl, or cyclopropyl; and wherein X is bromo or chloro, or the pharmacologically acceptable acid addition salts thereof.
In order to produce the compounds of formula III, two processes are available which can be illustratively represented as follows: ##STR5## wherein A.sub.o is selected from the group consisting of --(CH.sub.2).sub.2 --; --(CH.sub.2).sub.3 --; ##STR6## wherein A'.sub.o is --(CH.sub.2).sub.4 or --(CH.sub.2).sub.5 --; wherein X is bromo or chloro; wherein X' is chloro, bromo or iodo and wherein R is ethyl, cyclopropyl or vinyl.
The more preferred end products used in the subsequent formulations are of the formula IIIA: ##STR7## where A is selected from the group consisting of --(CH.sub.2).sub.2 --; --(CH.sub.2).sub.3 --; --(CH.sub.2).sub.4 -- and --(CH.sub.2).sub.5 --; ##STR8## and wherein X is bromo or chloro.
The most preferred compounds used in the subsequent formulations are of the formula IIIB: ##STR9## wherein A' is ethylene or trimethylene.
Compounds of similar structures are shown in U.S. Pat. No. 3,016,281; however, these patented compounds are analgesics. The present compounds on the other hand are anti-depressive.
U.S. Pat. No. 3,573,320 discloses but does not claim anti-depressant agents of the formula: ##STR10## wherein B is oxygen or sulfur; R.sub.2 is --(CH.sub.2).sub.n ##STR11## in which n is 2 or 3, R.sub.4 and R.sub.5 are H or alkyl, or ##STR12## is morpholino, piperidino, pyrrolidino or piperazino, R.sub.3 is alkyl, aryl, etc.
U.S. Pat. No. 3,234,276 and French Patent No. 2,073,286 (Chem. Abstracts 77,88108) also claim related products, but for different uses.
However, none of the references above read on the anti-depressant activity of compounds of Formula III.
The process I of this invention comprises: heating a mole equivalent of 3,4-dihaloaniline I with about 1/2 to 1 mole equivalent of a dimethylaminoalkyl halide to give compound II, (the excess of compound I provides the base to accept the hydrogen halide moiety generated in this reaction) and acylating compound II, e.g., with the chlorides or bromides of propionic acid, acrylic acid or cyclopropanecarboxylic acid in the presence of a base, or with propionic anhydride to obtain the corresponding compound of Formula IV.
The process II of this invention comprises: heating a mole equivalent of 3,4-dihaloaniline with about 1 mole equivalent of N,N-dimethylamino halobutyramide or -valeramide to give compound V; reducing V with metal hydride to give compound VI; and acylating compound VI to give compound VII.
The metal hydrides herein used include: lithium aluminum hydride, sodium cyanoborohydride, borane, diborane.
The invention also encompasses the pharmacologically acceptable acid addition salts of the compounds of formula III (including the preferred compounds of formulae IIIA and IIIB). These salts comprise the hydrochlorides, hydrobromides, sulfates, malates, maleates, tartrates, lactates, citrates, cyclohexanesulfamates, methanesulfonates and the like which are prepared by reacting compounds of Formula III with a stoichiometrically calculated amount of the selected acid, in aqueous or ethereal solution, and finally evaporating the solvent.
The invention also comprises the use of the compounds of Formula III or the salts thereof, described above, in pharmaceutical formulations for treating depressions of endogenous and/or exogenous character.